Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

• lumbar spinal fusion When conservative treatment has failed, lumbar spinal fusion has been accepted as an option for patients with severe discogenic pain from instability and lumbar degenerative pathologies.
• the ultimate goal of fusion is the elimination of movement between the motion segments that will reduce or abolish the pain.
• Spinal fusion is the uniting of two or more motion segments (disc space and paired facet joint, i.e., a single motion segment) together by the placement of bone graft.
• This fusion process is not only the immediate result of placement of a cage bone graft connecting the two motion segments but also the result of the body's healing process resulting in the formation of new bone material. Therefore, new approaches in lumbar fusion surgery attempt to enhance the body's healing potential to promote this fusion process.
• HA hydroxyapatite
• TCP tricalcium phosphate
• BCP biphasic calcium phosphate
• collagen and demineralized bone matrix.
• bioresorbable cages made of polylactic acid with an elasticity modulus resembling that of vertebral bone could be used as a temporary carrier for synthetic filling material.
• Posterolateral spine fusion is a very challenging area for bone formation/regeneration. Osteoconductive bone graft materials do not usually perform well in such an environment. Thus, compositions and systems for bone fusion are still needed.
• the present invention is directed to methods, compositions, systems, and medical devices for fusing bone, particularly fusing vertebrae within the spine of a subject.
• the bone-fusion composition includes a matrix for bone formation and a growth factor protector and potentiator.
• Such compositions can be used in systems and medical devices that include cage devices for fusing vertebrae, for example.
• the matrix for bone formation preferably includes an osteoconductive carrier such as a calcium phosphate, particularly biphasic calcium phosphate, although other matrices can be used including, for example, collagen, alginate, or combinations thereof.
• an osteoconductive carrier such as a calcium phosphate, particularly biphasic calcium phosphate, although other matrices can be used including, for example, collagen, alginate, or combinations thereof.
• the bone-fusion composition can also be used in conjunction with a cage device (e.g., an interbody fusion cage), which can be made of a resorbable or nonresorbable material.
• a cage device e.g., an interbody fusion cage
• the present invention provides a bone-fusion system that includes a bone-fusion composition, wherein the bone-fusion composition includes biphasic calcium phosphate, and a polymer having the general formula (I): A a X x Y y wherein:
• A represents a monomer which is substituted with independently selected X and Y groups
• X represents a carboxyl group bonded to monomer A and is contained within a group according to the following formula: —R—COO—R′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′ represents a hydrogen atom, Y, or a cation;
• Y represents a sulfate of sulfonate group bonded to a monomer A and is contained within a group according to one of the following formulas: —R—O—SO 3 —R′′, —R—N—SO 3 —R′′, —R—SO 3 —R′′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′′ represents a hydrogen atom or a cation;
• y represents a substitution rate of the monomers A by the groups Y, which is 30% to 150%.
• the present invention provides a bone-fusion system that includes a bone-fusion composition, wherein the bone-fusion composition includes biphasic calcium phosphate and a polymer having the general formula (II): A a X x Y y Z z wherein:
• A represents a monomer based on glucose which is substituted with independently selected X, Y, and Z groups;
• X represents a carboxyl group bonded to monomer A and is contained within a group according to the following formula: —R—COO—R′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can
• Y represents a sulfate of sulfonate group bonded to a monomer A and is contained within a group according to one of the following formulas: —R—O—SO 3 —R′′, —R—N—SO 3 —R′′, —R—SO 3 —R′′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′′ represents a hydrogen atom, Z, or a cation;
• Z is selected from the group consisting of amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, and nucleotide addressing sequences;
• x represents a substitution rate of the monomer A by the groups X, which is 20% to 150%;
• a method of fusing bone includes: providing a bone-fusion system of the present invention that includes a bone-fusion composition; placing the composition in contact with bone to be fused; and allowing the bone-fusion composition to harden and fuse the bone.
• a method of fusing bone includes: providing a bone-fusion system that includes a bone-fusion composition, wherein the bone-fusion composition includes: a growth factor protector and potentiator; and a matrix for bone formation; placing the composition in contact with bone to be fused; and allowing the bone-fusion composition to harden and fuse the bone.
• a medical device in one embodiment, includes a cage device and a bone-fusion composition, wherein the bone-fusion composition includes: a growth factor protector and potentiator; and a matrix for bone formation.
• bone fusion refers to permanently joining bone in order to prevent motion, particularly between vertebrae.
• Spinal fusion is the permanent joining of two or more motion segments (disc space and paired facet joint).
• bone means entire bones or bone fragments.
• compositions that comprises “a” polymer can be interpreted to mean that the composition includes “one or more” polymers.
• the present invention provides a bone-fusion composition that includes a matrix for bone formation and a growth factor protector and potentiator. Such compositions are particularly useful in methods for fusing vertebrae within the spine of a subject.
• the compositions can also be used in systems and medical devices that include cage devices (which can be made of materials that are resorbable or nonresorbable in the body of a subject).
• the matrix for bone formation preferably includes an osteoconductive carrier such as a calcium phosphate, particularly biphasic calcium phosphate, although other matrices can be used including, for example, collagen, alginate, or combinations thereof.
• an osteoconductive carrier such as a calcium phosphate, particularly biphasic calcium phosphate, although other matrices can be used including, for example, collagen, alginate, or combinations thereof.
• the matrix for bone formation is biphasic calcium phosphate.
• such materials are resorbable in the body of a subject.
• BCP biphasic calcium phosphate
• BICALPHOS or MASTERGRAFT from Medtronic Sofamor Danek, Memphis, Term. It is a bioresorbable ceramic with a well-defined macroporous structure. The controlled porosity and the presence of interconnection between all the pores can facilitate tissue/cells proliferation inside the material. It is believed that the presence of a controlled specific pore size and the interconnectivity of the pores is that which gives the BCP its osteoconductive properties.
• the bioactive concept of BCP is based on an optimal balance of the more stable phase of HA (calcium hydroxyapatite) and the more soluble TCP (tricalcium phosphate).
• the growth factor protector and potentiator is a material (e.g., polymer) that will promote cellular/tissue proliferation, and more particularly will sustain and promote bone fusion in spinal surgery. Preferred materials mimic the properties of heparin toward heparin binding growth factors.
• the growth factor protector and potentiator is a heparin-binding growth factor protector and potentiator (preferably, a dextran derivative).
• the growth factor protector and potentiator can be used in a variety of formats. For example, it can be used in solution and administered to the appropriate site via injection. It can be adsorbed onto or covalently bonded to a carrier (e.g., granular material) and/or cage device prior to implantation.
• a carrier e.g., granular material
• the growth factor protector and potentiator is preferably selected from the polymers described in U.S. Pat. App. Pub. Nos. 2001/0021758 or 2001/0023246, or U.S. Pat. No. 6,689,741.
• This material which is often referred to as RGTA (ReGeneraTing Agents)
• RGTA ReGeneraTing Agents
• RGTAs are functional analogues of heparan sulfate proteoglycans and protect various growth factors from proteolytic degradation, and even enhance their biological activities.
• the growth factor protector and potentiator can be bound to the matrix for bone formation, either chemically (e.g., covalently) or physically (e.g., adsorbed). If chemically bound, the growth factor protector and potentiator could be coupled to the matrix for bone formation using a wide variety of coupling chemistries. Preferably, for the preferred embodiments of the growth factor protector and potentiator and matrix for bone formation described herein, this can be done using the well-known ester coupling method.
• the ester-coupling agent is a carbodiimide. Carbodiimide is generally utilized as a carboxyl-activating agent for amide bonding with primary amines.
• the growth factor protector and potentiator is a polymer having the general formula (I): A a X x Y y wherein:
• A represents a monomer which is substituted with independently selected X and Y groups
• X represents a carboxyl group bonded to monomer A and is contained within a group according to the following formula: —R—COO—R′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′ represents a hydrogen atom, Y, or a cation;
• Y represents a sulfate of sulfonate group bonded to a monomer A and is contained within a group according to one of the following formulas: —R—O—SO 3 —R′′, —R—N—SO 3 —R′′, —R—SO 3 —R′′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′′ represents a hydrogen atom or a cation;
• a represents the number of the monomer A such that the mass of said polymers of formula (I) is greater than 5,000 daltons;
• x represents a substitution rate of the monomer A by the groups X, which is 20% to 150%;
• y represents a substitution rate of the monomer A by the groups Y, which is 30% to 150%.
• the growth factor protector and potentiator can include a bound active agent (e.g., amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, and nucleotide addressing sequences).
• a bound active agent e.g., amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, and nucleotide addressing sequences.
• the growth factor protector and potentiator is a polymer having the general formula (II): A a X x Y y Z z wherein:
• A represents a monomer based on glucose which is substituted with independently selected X, Y, and Z groups;
• X represents a carboxyl group bonded to monomer A and is contained within a group according to the following formula: —R—COO—R′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′ represents a hydrogen atom, Y, Z, or a cation;
• Y represents a sulfate of sulfonate group bonded to a monomer A and is contained within a group according to one of the following formulas: —R—O—SO 3 —R′′, —R—N—SO 3 —R′′, —R—SO 3 —R′′, in which R is a bond or an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and which can contain one or more aromatic rings except for benzylamine and benzylamine sulfonate, and R′′ represents a hydrogen atom, Z, or a cation;
• Z is selected from the group consisting of amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, and nucleotide addressing sequences;
• a represents the number of the monomer A such that the mass of said polymers of formula (II) is greater than 5,000 daltons;
• x represents a substitution rate of the monomer A by the groups X, which is 20% to 150%;
• y represents a substitution rate of the monomer A by the groups Y, which is 30% to 150%;
• z represents the rate of substitution of the monomer A by groups Z, which is 0 to 50%.
• the bone-fusion system can also include a cage device, particularly an interbody fusion cage for spinal fusion (i.e., an arthrodesis) that is used in combination with the bone-fusion composition.
• a cage device particularly an interbody fusion cage for spinal fusion (i.e., an arthrodesis) that is used in combination with the bone-fusion composition.
• the matrix e.g., biphasic calcium phosphate
• bound or adsorbed growth factor protector and potentiator e.g., a polymer of the formula A a X x Y y described above
• the cage device can be made of a resorbable material or a nonresorbable material.
• the bone-fusion composition can further include a growth factor, either in admixture therewith or as part of the growth factor protector and potentiator as described in U.S. Pat. App. Pub. Nos. 2001/0021758 or 2001/0023246, or U.S. Pat. No. 6,689,741.
• Z is derived from a growth factor.
• the growth factor is preferably selected from the group consisting of heparin-binding growth factors (e.g., BMP-2 or bone morphogenic protein), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and combinations thereof.
• the present invention also provides methods for fusing bone.
• bone fusion refers to permanently joining bone in order to prevent motion, particularly between vertebrae.
• bone means entire bones or bone fragments.
• such methods of fusing bone involve: providing a bone-fusion system comprising a bone-fusion composition, wherein the bone-fusion composition includes; a growth factor protector and potentiator; and a matrix for bone formation; placing the composition in contact with bone to be fused; and allowing the bone-fusion composition to harden and fuse the bone.
• the present invention also provides medical devices that include a cage device and a bone-fusion composition, wherein the bone-fusion composition comprises: a growth factor protector and potentiator; and a matrix for bone formation.
• a cage device and a bone-fusion composition
• the bone-fusion composition comprises: a growth factor protector and potentiator; and a matrix for bone formation.
• Such cage devices are well known to one of skill in the art and could be readily used with a composition of the present invention without undue experimentation.
• the purpose of this study was to evaluate the performance and local tolerance of a bone factor RGTA mixed with a bone substitute (BCP) implanted for 6 weeks to induce bone lumbar fusion in 53 New Zealand rabbits.
• This test treatment was compared to five other treatment variations: BCP (3 cubic centimeters (cm 3 )) alone; autologous bone alone used at a volume of 3 cm 3 or 1.5 cm 3 ; autologous bone (1.5 cm 3 ) mixed with BCP (1.5 cm 3 ); and autologous bone (1.5 cm 3 ) mixed with BPC (3 cm 3 ) and RGTA.
• BICALPHOS from Medtronic Sofamor Danek is a synthetic bone substitute with a well-defined macroporous structure (approximately 80% porosity, pores of 400-600 nanometer (nm) diameters with inter-connections of 120-150 micron diameters). Sterile BCP granules were used in this study.
• RGTA from Regentech SAS (Paris, France) is a heparan-like polymer, synthesized from dextran by a controlled sequential substitution of its glucose units, as described in U.S. Pat. No. 6,689,741, Example 2.
• Rabbits were implanted with autologous bone under a volume of 3 cm 3 per site, obtained from rabbit iliac crest.
• BCP BCP granules were transferred into a 12 mL sterile tube by the Sponsor and the desired amount (3 cm 3 or 1.5 cm 3 ) were measured. Prior to implantation, 5 mL of 0.9% NaCl was added to the BCP granules and mixed for 30 minutes.
• Autologous bone after fascial incisions over the iliac crest, autologous bone chips were harvested from the corticocancellous bone of the iliac crests. The harvested bone was transferred into a sterile bowl and broken down into homogeneously small chips. The bone chips were then transferred into a 12 mL tube. 1.5 cm 3 or 3 cm 3 were then implanted into the corresponding animals.
• Autologous bone+BCP the autologous bone was prepared as described. The determined amount of autologous bone (1.5 cm 3 ) was mixed with 1.5 cm 3 of BCP granules and implanted.
• BCP+RGTA 3 cm 3 of BCP granules were mixed with 5 mL of a filtered solution of 100 ⁇ g/mL RGTA and shaken for 30 minutes prior to implantation.
• Autologous bone+BCP+RGTA the autologous bone was prepared as described. 1.5 cm 3 of autologous bone were mixed with 1.5 cm 3 of BCP containing 2.5 mL of a filtered 100 ⁇ g/mL solution of RGTA.
• Each animal was anesthetized with 1 mL xylazine hydrochloride commercially available under the trade designation ROMPUN 2%, BAYER AG, (Germany) and 1 mL ketamine (commercially available under the trade designation IMALGENE 500, MERIAL, France) by intramuscular route.
• ROMPUN 2% commercially available under the trade designation ROMPUN 2%
• BAYER AG Germany
• 1 mL ketamine commercially available under the trade designation IMALGENE 500, MERIAL, France
• the surgical site of the animals was clipped free or furs scrubbed with a germicidal soap (commercially available under the trade designation VETEDINE, VETOQUINOL, France) and disinfected with povidone iodine (commercially available under the trade designation VETEDINE solution, VETOQUINOL, France).
• VETEDINE germicidal soap
• povidone iodine commercially available under the trade designation VETEDINE solution, VETOQUINOL, France.
• the animal received warm intravenously (I.V.) fluids to prevent dehydratation and help maintain normal body temperature. The reflexes, body temperature and heart rate were also monitored regularly.
• the surgical procedure was performed under standard aseptic techniques.
• the L5-L6 vertebral level was estimated by palpation of the iliac crests.
• a dorsal midline skin incision was made through the skin and two paramedian fascial incisions were performed through the lumbodorsal fascia.
• the intermuscular plane between the multifidus and longissimus muscles was separated to expose the transverse processes of L5, L6 and the intertransverse membrane.
• the transverse processes were decorticated using a surgical drilling tool and two identical defects were created symmetrically on each transverse proceedings.
• the prepared materials were placed without excessive compression between the transverse processes in the paraspinal bed on each side of the spine. When all implants were in place, the fascial incisions were closed with absorbable sutures and the skin incision was closed using metallic staples.
• Postero-anterior radiographs of the L5-L6 lumbar spine were obtained under general anesthesia immediately after surgery, after two, and after four weeks post implantation as well as at sacrifice. The radiographs were then analyzed and the level of fusion was graded using a semi-quantitative grading scale: 0: absence; 1: slight; 2: moderate; 3: marked; 4: complete.
• the lumbar spines were manually palpated at the level of the treated motion segment and at the levels of adjacent motion segments proximally and distally. Each motion segment was graded as solid or not solid (if any motion was present).
• the lumbar specimens were electro-decalcified.
• the samples were dehydrated in alcohol baths of increasing concentrations and embedded in paraffin blocks.
• Three parasagittal (longitudinal) sections of 5 ⁇ m were cut using a microtom (MICROM, France) in each transverse processes site and through the vertebra arch. Two of the sections were stained with hematoxylin, eosin, and saffron. The remaining section was stained with a Masson trichrome.
• the Emory score or grading scale was used in this study to evaluate the different treatments and treatment sites.
• the Emory grading scale is an established histological scoring scale based upon a 0 to 7 score of fibrous tissue, fibrocartilage, and bone content of the fusion mass. This scale was modified in order to adequately take into account the different properties of the test article and control articles evaluated in this study.
• test treatment [BCP (3 cm 3 )+RGTA; group 6] provided a good level of fusion.
• the highest level of fusion was obtained by the positive control treatment [autologous bone (3 cm 3 ); group 1] and the autologous bone (1.5 cm 3 ) mixed with BCP (1.5 cm 3 ); group 4.
• BCP alone showed limited performances, similar to the low volume (1.5 cm 3 ) of autologous bone group.
• test treatment (BCP (3 cm 3 )+RGTA) showed a faster fusion than the other treatments, except the 3 cm 3 autologous bone treatment.
• Group 2-Autologous bone (1.5 cm 3 ): a complete fusion, where bone spanned the defect area was not observed for this treatment group.
• the periosteal reaction extended into the implant sites and lead to Modified Emory scores of 6 for four of the ten implant sites for this treatment group around the vertebral arch.
• the osteoconduction correlated to the amount of periosteal reaction present. Less newly formed bone was observed between the transverse processes. The placement, space between the bone chips, and size of the bone chips were slightly more consistent in the implant area for this treatment group.
• the amount of fibrous tissue was greater than newly formed bone. Inflammation was located peripheral to the implant site in one animal.
• Group 3-BCP (3 cm 3 ): the BCP consisted of an almost translucent granular material (decalcified material) with consistent large round open (pore-like) areas. The granular matrix had distinct edges and somewhat regular shape. Some of the granular matrix was interconnected whereas in other areas individual pieces of the matrix were present. The granular material was better distributed in the implanted sites compared to the 2 previous sites. Near the vertebrae arch and between the transverse processes, the tissue reaction extended into the round spaces of the matrix to form discrete bony pearls. In other areas fibrocartilage was within the round spaces of the matrix. In most sites the matrix spanned the entire implant area but the density was frequently noted to be decreased in the central areas of the implant site.
• the implanted material demonstrated very good osteoconductive properties.
• One site was scored 6 between the transverse processes and many of the sites in this treatment group had new bone extending throughout the length of the implant area.
• the central area of the implant sites (away and between the transverse processes) mostly contained fibrocartilage and fibrous tissue along with a lesser amount of new bone.
• the fibrous tissue, fibrocartilage and newly formed bone tissue were present in approximative equal amount. Neovessels seemed to increase with area of marked bone ingrowth. This treatment performed better than the previous two treatments.
• Group 5-Autologous bone (1.5 cm 3 )+BCP (1.5 cm 3 )+RGTA four of the eight-implant sites were associated with large accumulations of inflammatory cells. This affected the performance of the treatment. The inflammation involved the soft tissue and penetrated into the implant site but the inflammation did not involve the entire implant site. With no accumulations of inflammatory cells observed in the remaining animals, the inflammation observed was most likely not directly associated with the test article. The BCP and the bone chips from the autologous graft were not well distributed throughout the implant site in this treatment group. Very little of the test article components were noted within the central areas of the implant sites.
• this treatment performed similar to the 1.5 cm 3 of autologous graft treatment (treatment 2) and better than the 3.0 cm 3 of autologous graft (treatment 1) along the vertebral arch as well as between the transverse processes.
• the 1.5 cm 3 of BCP, 1.5 cm 3 of autologous graft and RGTA treatment sites were complicated by inflammation in 50% of the treated sites.
• the inflammation observed in this study (including in group 5) was not considered to be directly related to the treatment received. This was made evident by the primary location of the inflammation to the periphery of the implant areas, as well as the observation that the entire implanted test article was not affected. Even though a small sample size was used in this study, the observed trends in the Modified Emory score were considered to be of biological significance.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Materials Engineering (AREA)
• Engineering & Computer Science (AREA)
• Dermatology (AREA)
• Medicinal Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Composite Materials (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Materials For Medical Uses (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (1)

Publications (1)

Family

ID=37105519

Family Applications (1)

Country Status (2)

Cited By (5)

Citations (3)

Family Cites Families (3)

• 2005
  • 2005-05-16 US US11/129,977 patent/US20060257449A1/en not_active Abandoned
• 2006
  • 2006-05-11 WO PCT/US2006/018343 patent/WO2006124545A2/fr not_active Ceased

Patent Citations (3)

Also Published As

Similar Documents

Legal Events